Calicheamicin: Difference between revisions

Latest revision as of 16:14, 26 March 2025

A potent antitumor antibiotic

Calicheamicin is a potent antibiotic and antitumor agent belonging to the class of enediynes. It is produced by the bacterium Micromonospora echinospora and is known for its ability to cleave DNA with high specificity and efficiency. Calicheamicin is one of the most potent cytotoxic agents known and has been utilized in the development of antibody-drug conjugates for targeted cancer therapy.

Structure[edit]

Calicheamicin is characterized by its unique molecular structure, which includes an enediyne core. This core is responsible for its DNA-cleaving activity. The molecule also contains a trisulfide linkage and a sugar moiety, which contribute to its binding affinity and specificity for DNA. The enediyne core undergoes a Bergman cyclization to form a highly reactive diradical species that abstracts hydrogen atoms from the DNA backbone, leading to strand scission.

Mechanism of Action[edit]

The mechanism of action of calicheamicin involves its binding to the minor groove of DNA, followed by activation of the enediyne core. Upon activation, the enediyne undergoes a cycloaromatization reaction, generating a diradical species. This diradical abstracts hydrogen atoms from the deoxyribose sugar in the DNA backbone, resulting in double-strand breaks. These breaks are lethal to cells, making calicheamicin an effective cytotoxic agent.

Clinical Applications[edit]

Calicheamicin has been utilized in the development of gemtuzumab ozogamicin, an antibody-drug conjugate used in the treatment of acute myeloid leukemia (AML). In this conjugate, calicheamicin is linked to an antibody that targets the CD33 antigen on leukemia cells, allowing for targeted delivery of the cytotoxic agent. This targeted approach minimizes damage to normal cells and enhances the therapeutic index of the drug.

Challenges and Research[edit]

Despite its potent activity, the clinical use of calicheamicin is limited by its toxicity and the development of resistance. Research is ongoing to develop new formulations and delivery methods to improve its therapeutic window. Efforts are also being made to engineer calicheamicin derivatives with improved selectivity and reduced side effects.

Related Pages[edit]

Types of antibacterials

This article is a medical stub. You can help WikiMD by expanding it!
Most recent articles Ongoing trials	Wikipedia

@@ Line 1: / Line 1: @@
-{{png-image}}
+{{Short description|A potent antitumor antibiotic}}
-'''Calicheamicin''' is a highly potent [[antibiotic]] and [[antineoplastic]] agent, belonging to the enediyne class of antibiotics. It is produced by the bacterium ''[[Micromonospora echinospora]]'' subsp. ''calichensis''. Calicheamicin works by binding to the minor groove of [[DNA]] and causing double-strand breaks, leading to cell death. This mechanism of action makes it one of the most powerful [[chemotherapeutic]] agents known, used particularly in the treatment of certain types of [[cancer]], such as [[acute myeloid leukemia]] (AML).
+[[File:Calicheamicin.png|Calicheamicin|thumb]]
+[[File:Calicheamicin_gamma_1_3D_spacefill.png|Calicheamicin gamma 1 3D spacefill|left|thumb]]
+[[File:Iterative_PKS.png|Iterative PKS|thumb]]
+[[File:Calicheamicin_pathway.png|Calicheamicin pathway|thumb]]
+'''Calicheamicin''' is a potent [[antibiotic]] and [[antitumor]] agent belonging to the class of [[enediynes]]. It is produced by the bacterium ''[[Micromonospora echinospora]]'' and is known for its ability to cleave [[DNA]] with high specificity and efficiency. Calicheamicin is one of the most potent cytotoxic agents known and has been utilized in the development of [[antibody-drug conjugates]] for targeted cancer therapy.
-The discovery of calicheamicin and its unique mode of action has led to the development of [[antibody-drug conjugates]] (ADCs), where calicheamicin is linked to a monoclonal antibody that specifically targets cancer cells. One such example is [[gemtuzumab ozogamicin]], an ADC that targets the CD33 antigen present on the surface of AML cells.
+===Structure===
+Calicheamicin is characterized by its unique molecular structure, which includes an enediyne core. This core is responsible for its DNA-cleaving activity. The molecule also contains a trisulfide linkage and a sugar moiety, which contribute to its binding affinity and specificity for DNA. The enediyne core undergoes a Bergman cyclization to form a highly reactive diradical species that abstracts hydrogen atoms from the DNA backbone, leading to strand scission.
-Despite its potent anticancer activity, the use of calicheamicin is limited by its significant toxicity to normal cells. Research is ongoing to develop strategies to target calicheamicin more selectively to cancer cells to minimize side effects.
+===Mechanism of Action===
+The mechanism of action of calicheamicin involves its binding to the minor groove of DNA, followed by activation of the enediyne core. Upon activation, the enediyne undergoes a cycloaromatization reaction, generating a diradical species. This diradical abstracts hydrogen atoms from the deoxyribose sugar in the DNA backbone, resulting in double-strand breaks. These breaks are lethal to cells, making calicheamicin an effective cytotoxic agent.
-== Pharmacology ==
+===Clinical Applications===
-Calicheamicin binds to the minor groove of DNA, where it undergoes a [[Michael addition]] reaction with the DNA. This reaction is facilitated by the presence of a [[trisulfide]] moiety in calicheamicin, which, upon reduction, forms a highly reactive diradical species. This diradical species attacks the DNA, causing strand breaks and leading to apoptosis of the cell.
+Calicheamicin has been utilized in the development of [[gemtuzumab ozogamicin]], an antibody-drug conjugate used in the treatment of [[acute myeloid leukemia]] (AML). In this conjugate, calicheamicin is linked to an antibody that targets the CD33 antigen on leukemia cells, allowing for targeted delivery of the cytotoxic agent. This targeted approach minimizes damage to normal cells and enhances the therapeutic index of the drug.
-== Clinical Use ==
+===Challenges and Research===
-The clinical use of calicheamicin is primarily through its incorporation into antibody-drug conjugates. Gemtuzumab ozogamicin, for example, has been used in the treatment of acute myeloid leukemia, offering a targeted therapy option that brings the potent cytotoxic effects of calicheamicin to cancer cells expressing the CD33 antigen.
+Despite its potent activity, the clinical use of calicheamicin is limited by its toxicity and the development of resistance. Research is ongoing to develop new formulations and delivery methods to improve its therapeutic window. Efforts are also being made to engineer calicheamicin derivatives with improved selectivity and reduced side effects.
-== Side Effects ==
-The major limitation in the use of calicheamicin is its toxicity, which can lead to severe side effects such as [[myelosuppression]], [[liver toxicity]], and [[vascular leak syndrome]]. Efforts to mitigate these side effects include the development of more selective delivery mechanisms and the use of lower doses in combination therapies.
-== Research and Development ==
-Ongoing research focuses on improving the therapeutic index of calicheamicin through the development of new antibody-drug conjugates and exploring its potential in treating other types of cancer. Additionally, studies aim to better understand the mechanism of action of calicheamicin and its interaction with DNA, which could lead to the design of more effective and less toxic analogs.
+==Related Pages==
+* [[Enediyne]]
+* [[Antibody-drug conjugate]]
+* [[Acute myeloid leukemia]]
+* [[DNA]]
+* [[Antibiotic]]
+{{Antibiotics}}
+{{Chemotherapy}}
+{{stub}}
 [[Category:Antibiotics]]
-[[Category:Antineoplastic agents]]
+[[Category:Chemotherapy]]
-{{medicine-stub}}
+[[Category:Enediynes]]
-<gallery>
-File:Calicheamicin Iterative_PKS.png
-File:Calicheamicin_pathway.png
-</gallery>
-<gallery>
-File:Calicheamicin.png|Calicheamicin
-File:Calicheamicin_gamma_1_3D_spacefill.png|Calicheamicin gamma 1 3D spacefill
-File:Iterative_PKS.png|Iterative PKS
-File:Calicheamicin_pathway.png|Calicheamicin pathway
-</gallery>